Secretory pathway antagonism by calicivirus homologues of Norwalk virus nonstructural protein p22 is restricted to noroviruses

Tyler M Sharp,Kazuhiko Katayama,Sue E Crawford,Mary K Estes,Frederick H Neill,Budi Utama,Nadim J Ajami,Robert L Atmar

doi:10.1186/1743-422x-9-181

Abstract

BackgroundOur previous report that the Norwalk virus nonstructural protein p22 is an antagonist of the cellular secretory pathway suggests a new aspect of norovirus/host interaction. To explore conservation of function of this highly divergent calicivirus protein, we examined the effects of p22 homologues from four human and two murine noroviruses, and feline calicivirus on the secretory pathway.FindingsAll human noroviruses examined induced Golgi disruption and inhibited protein secretion, with the genogroup II.4 Houston virus being the most potent antagonist. Genogroup II.6 viruses have a conserved mutation in the mimic of an Endoplasmic Reticulum export signal (MERES) motif that is highly conserved in human norovirus homologues of p22 and is critical for secretory pathway antagonism, and these viruses had reduced levels of Golgi disruption and inhibition of protein secretion. p22 homologues from both persistent and nonpersistent strains of murine norovirus induced Golgi disruption, but only mildly inhibited cellular protein secretion. Feline calicivirus p30 did not induce Golgi disruption or inhibit cellular protein secretion.ConclusionsThese differences confirm a norovirus-specific effect on host cell secretory pathway antagonism by homologues of p22, which may affect viral replication and/or cellular pathogenesis.

Highlights

Our previous report that the Norwalk virus nonstructural protein p22 is an antagonist of the cellular secretory pathway suggests a new aspect of norovirus/host interaction
These differences confirm a norovirus-specific effect on host cell secretory pathway antagonism by homologues of p22, which may affect viral replication and/or cellular pathogenesis
Genogroup V contains murine norovirus (MNV), which is lethal to STAT1−/− mice [5]

Summary

Introduction

Our previous report that the Norwalk virus nonstructural protein p22 is an antagonist of the cellular secretory pathway suggests a new aspect of norovirus/host interaction. Since NV, MNV and FCV all induce Golgi disruption [6,7,8], we compared calicivirus homologues of p22 for the following: sequence similarity, including conserved motifs; cellular distribution and location following expression; ability to induce Golgi disassembly; and inhibition of cellular protein secretion. A conserved YXΦESDG MERES motif (where X is any amino acid and Φ is a bulky, hydrophobic residue [e.g. M, I or L]) was present in 92% (65 of 72) of NoV p22L, of which the Y and E residues are most important to secretory pathway antagonism [6].

Results

Conclusion